Cytochrome P450 2C19 (CYP2C19) Pharmacogenetic Competency

Updated on 6/2015 Pre-test Question # 1

A patient has a reported pharmacogenetic test result of CYP2C19 *1/*12. What is the assigned phenotype? a) Ultra-rapid metabolizer (UM) b) Intermediate metabolizer (IM) c) Poor metabolizer (PM) d) Indeterminate Pre-test Question # 2

A patient with a reported pharmacogenetic test result of CYP2C19 *2A/*2A who is receiving clopidogrel is at risk of suffering from an adverse cardiovascular event (e.g. thrombosis) due to treatment failure. a) Increased b) Moderate c) Decreased

Pre-test Question # 3

JH has an indication to start clopidogrel therapy. He has a reported pharmacogenetic test result of CYP2C19 *2A/*3. What is your recommendation to the physician regarding the use of clopidogrel? a) Use clopidogrel at an increased dose b) Use clopidogrel at a reduced dose c) Use clopidogrel at a standard dose d) Use an alternative antiplatelet agent Pre-test Question # 4

Which of the following statements is most correct about a CYP2C19 *17/*17 genotype? a) Patients convert clopidogrel to an inactive metabolite to a greater extent than *1/*1 and therefore a decrease in clopidogrel dose is recommended b) Patients convert clopidogrel to an active metabolite to a greater extent than *1/*1 but no change in clopidogrel dose is recommended c) Patients convert clopidogrel to an active metabolite to a lesser extent than *1/*1 and therefore a decrease in clopidogrel dose is recommended d) Patients convert clopidogrel to an active metabolite to a lesser extent than *1/*1 and therefore a change in therapy is recommended Objectives

• Upon completion of this competency, participants will be able to: – Recognize the different CYP2C19 allele variants – Describe the different CYP2C19 phenotypes – Assign the correct phenotype based upon the allele variants – Make therapeutic recommendations for clopidogrel dosing based on a patient's predicted CYP2C19 phenotype Patient Case

• A 74-year-old patient with severe coronary artery disease started on clopidogrel following a percutaneous coronary intervention (PCI). • After multiple episodes of restenosis, clopidogrel resistance was suspected. • Platelet reactivity testing measured while on clopidogrel returned was high (suggestive of resistance). • CYP2C19 genotyping revealed that the patient was homozygous for two non-functional alleles (*2/*2 genotype). The patient was classified as having a CYP2C19 poor metabolizer phenotype. • Switched to prasugrel, reduction in platelet reactivity by 86% and no cardiovascular events since switching agents.

Rai M, et al. Conn Med. 2012;76(5):267-72. CYP2C19 Pharmacogenetics CYP2C19

• CYP2C19 is an enzyme that metabolizes some commonly prescribed drugs

• Metabolism by CYP2C19 can either activate or inactivate a drug – Clopidogrel is a prodrug that is metabolized to an active form by CYP2C19 – Amitriptyline is metabolized by CYP2C19 to a less active form

CYP2C19

• Genetic variations in the CYP2C19 gene may lead to changes in metabolic activity of the CYP2C19 enzyme (increased or reduced function)

CYP2C19 Allele Variants

• CYP2C19 alleles are characterized into different groups: – Wild-type (normal function) alleles – Reduced function alleles – Increased function alleles – Uncharacterized alleles CYP2C19 Allele Variants

• CYP2C19 wild-type (normal function) allele: – This allele encodes for CYP2C19 enzymes with normal metabolic function – *1

Scott SA, et al. Clin Pharmacol Ther. 2013;94(3):317-23. CYP2C19 Allele Variants

• Certain CYP2C19 alleles are characterized as reduced function alleles – These alleles will encode for a CYP2C19 enzyme that has little or no metabolic function

• Reduced function CYP2C19 alleles include: – *2,*2A, *2B, *3, *4, *5, *6, *7, *8

Scott SA, et al. Clin Pharmacol Ther. 2013;94(3):317-23. CYP2C19 Allele Variants

• CYP2C19 has an allele characterized by a increased expression of the enzyme – This results in increased CYP2C19 metabolic activity compared to the wild-type (normal function) allele

• The CYP2C19 gain-of-function allele that is test for the most in clinical practice is the *17 allele

Scott SA, et al. Clin Pharmacol Ther. 2013;94(3):317-23. CYP2C19 Allele Variants

• For certain CYP2C19 alleles, the function of the enzyme is unknown and considered uncharacterized

• CYP2C19 uncharacterized alleles include: – *9, *10, *12, *13, *14,*15

Scott SA, et al. Clin Pharmacol Ther. 2013;94(3):317-23. www.pharmgkb.org Assigning a CYP2C19 Phenotype CYP2C19 Phenotypes

• The assignment of CYP2C19 phenotype is based on the two alleles that the patient carries (also called genotype or diplotype) • There are four CYP2C19 phenotypes — Ultra-rapid metabolizer (UM) — Extensive metabolizer (EM) — Intermediate metabolizer (IM) — Poor metabolizer (PM)

Scott SA, et al. Clin Pharmacol Ther. 2013;94(3):317-23. CYP2C19 Phenotypes

Phenotype Definition • Two copies of an increased function allele. Ultra-rapid • One copy of a normal function allele and one copy of an increased function Metabolizer (UM) allele. Extensive Metabolizer • Two copies of a normal function allele. (EM) • One copy of a reduced function allele and one copy of a normal function Intermediate allele. Metabolizer (IM) • One copy of an increased function allele (*17) with one copy of a reduced function allele (either *2, *2A and *2B).1 Poor Metabolizer • Two copies of a reduced function allele. (PM) • Two copies of an indeterminate function allele. • One copy of an indeterminate function allele with one copy of a known Indeterminate function allele. • One copy of an increased function allele with one copy of a reduced function allele (other than *2, *2A and *2B). 1. As per the CYP2C19/Clopidogrel CPIC guideline update (2013): The currently available evidence indicates that the *17 gain-of-function allele is unable to completely compensate for the *2 loss-of-function allele; however, these data have not been consistently replicated and is therefore a provisional classification. CYP2C19 Phenotypes

• Ultra-rapid Metabolizers (UM) — Have CYP2C19 enzyme function higher than normal — Approximately 17% of the population — Diplotype examples: • *17/*17 • *1/*17

CYP2C19 Phenotypes

• Extensive (normal) metabolizers (EM) — Have normal CYP2C19 enzyme function — Homozygous wild-type/normal — Approximately 43% of the population — Patient carrying two functional alleles — Diplotype examples: • *1/*1

CYP2C19 Phenotypes

• Intermediate metabolizers (IM) — Have decreased CYP2C19 enzyme function. The activity is in between extensive and poor metabolizer patients — Approximately 30% of the population — Diplotype examples: • *1/*2A • *2A/*17

CYP2C19 Phenotypes

• Poor metabolizers (PM) — Have little or no CYP2C19 enzyme function — Approximately 10% of the population — Patient carrying two reduced-function alleles — Diplotype examples: • *2A/*2A • *2A/*2B CYP2C19 Phenotypes

• Indeterminate • The expected phenotype cannot be determined based upon the CYP2C19 genotype result • For example, a patient may have two copies of an indeterminate function allele or one copy of an indeterminate function allele and one copy of a known function allele • *1/*12 • *12/*14 CYP2C19 Phenotypes

• Phenotypes associated with *17 allele – Only a few diplotypes which include the *17 allele have known functional activity: • *1/*17 is assigned an ultra-rapid metabolizer phenotype • *2/*17,*2A/*17 and *2B/*17 are assigned an intermediate function phenotype

– *17 plus any other allele is assigned an indeterminate phenotype

CYP2C19 Phenotypes

Ultrarapid Metabolizer- very high activity 10% 17% Extensive Metabolizer-normal activity 30% Intermediate Metabolizer- lower activity 43% Poor Metabolizer- low or no activity

* The exact percent of each phenotype group varies by ethnicity CYP2C19 Phenotypes

• CYP2C19 allele frequencies are dependent on ethnicity • *2 and *3 alleles are the most common variations – *2 allele: • ~30% of Asians • ~15% of Caucasians and African-Americans – *3 allele: • ~8% of Asians • Less than 1% in Caucasians and African-Americans • Prevalence of poor metabolizer phenotype: – Up to 25% of Asians – ~5% of Caucasians and African-Americans Gene-Based Dosing Recommendations Clopidogrel Clopidogrel

• Clopidogrel is an antiplatelet drug which inhibits ADP-induced platelet aggregation • Clopidogrel is commonly used in patients undergoing percutaneous coronary intervention (PCI) with stent placement • Other indications: – Acute coronary syndrome (ACS) – Stroke – Peripheral artery disease • The 2013 CPIC guideline on clopidogrel and CYP2C19 mainly focuses on ACS/PCI patients

Scott SA, et al. Clin Pharmacol Ther. 2013;94(3):317-23. Clopidogrel

• Clopidogrel is a pro-drug that requires hepatic bioactivation – 85% of the drug is hydrolyzed by carboxylesterase 1, leaving only 15% to be converted to the active form • The activation of clopidogrel is a two step process – Clopidogrel is converted to 2-oxoclopidogrel via CYP2C19 (45%), CYP1A2 (36%), and CYP2B6 (19%) – 2-oxoclopidogrel is converted to the active thiol metabolite via CYP3A4/5 (40%), CYP2B6 (33%), CYP2C19 (21%), and CYP2C9 (7%)

Scott SA, et al. Clin Pharmacol Ther. 2013;94(3):317-23. Kazui M, et al. Drug Metab Dispos. 2010;38:92-99. Clopidogrel

45%

21%

Sangkuhl K, et al. Pharmacogenet Genomics 2010;20:463-465. Clopidogrel

• Clopidogrel’s anti-platelet effect is closely related to CYP2C19 metabolism – Ultra-rapid metabolizers • Convert clopidogrel to the active metabolite at a greater extent than normal • Possible increase in antiplatelet activity • No recommended dosage change – Extensive metabolizers • Normal bioactivation • No recommended dosage change

Clopidogrel

• Clopidogrel anti-platelet effect is closely related to CYP2C19 metabolism – Intermediate metabolizers • Reduced bioactivation of clopidogrel to the active metabolite • Decreased platelet inhibition leading to increased residual platelet aggregation • Increased risk for adverse cardiovascular events (e.g., thrombosis) • CYP2C19 intermediate metabolizers generally should NOT receive clopidogrel • Consider alternatives such as prasugrel or ticagrelor

Clopidogrel

• Clopidogrel anti-platelet effect is closely related to CYP2C19 metabolism – Poor metabolizers • Poor bioactivation of clopidogrel to the active metabolite • Significantly reduced platelet inhibition leading to increased residual platelet aggregation • Significant increased risk for adverse cardiovascular events (e.g., thrombosis) • CYP2C19 poor metabolizers should NOT receive clopidogrel – Consider alternatives such as prasugrel or ticagrelor

Amitriptyline Amitriptyline

• CYP2C19 metabolizes amitriptyline to an active metabolite: nortriptyline

• CYP2D6 metabolizes amitriptyline and nortriptyline to less active hydroxy-metabolites

Hicks JK, et al. Clin Pharmacol Ther. 2013;93(5):402-8. Amitriptyline

• Amitriptyline’s efficacy is closely related to CYP2D6 and CYP2C19 metabolism – Ultra-rapid metabolizers of CYP2C19 and/or CYP2D6 • Convert amitriptyline to nortriptyline at a greater extent than extensive metabolizers (for CYP2C19) • Increased metabolism of amitriptyline to less active compounds compared to extensive metabolizers (for CYP2D6) • Lower plasma concentrations increase the probability of therapeutic failure • Consider an alternative agent not metabolized by CYP2C19

or CYP2D6 Hicks JK, et al. Clin Pharmacol Ther. 2013;93(5):402-8.

Amitriptyline

• Amitriptyline’s efficacy is closely related to CYP2D6 and CYP2C19 metabolism – Extensive metabolizers of CYP2C19 or CYP2D6 • Normal bioactivation • No recommended dosage change

Hicks JK, et al. Clin Pharmacol Ther. 2013;93(5):402-8. Amitriptyline

• Amitriptyline’s efficacy is closely related to CYP2D6 and CYP2C19 metabolism – Intermediate metabolizers of CYP2C19 or CYP2D6 • Reduced metabolism of amitriptyline when compared to extensive metabolizers • For CYP2D6 IM patients, consider a 25% reduction of the initial amitriptyline dose and titrate to effect. Utilize therapeutic drug monitoring as appropriate • For CYP2C19 IM patients, initiate therapy with the recommended starting doses of amitriptyline

Hicks JK, et al. Clin Pharmacol Ther. 2013;93(5):402-8. Amitriptyline

• Amitriptyline’s efficacy is closely related to CYP2D6 and CYP2C19 metabolism – Poor metabolizers of CYP2C19 or CYP2D6 • Greatly reduced metabolism of amitriptyline when compared to extensive metabolizers and an increased likelihood of side effects • Consider an alternative agent not metabolized by CYP2C19 or CYP2D6 • A table providing recommendations for dosing of amitriptyline according to the CYP2D6 and CYP2C19 genotype test results can be found here

Hicks JK, et al. Clin Pharmacol Ther. 2013;93(5):402-8. For More Information…

• For more information about CYP2C19 and clopidogrel dosing click here. • For more information about CYP2C19 and amitriptyline dosing click here. • For more information about pharmacogenetics visit the following website: www.pharmgkb.org • For more pharmacogenetic service implementation resources visit the following website: www.stjude.org/pg4kds/implement

Question # 1

Correct answer: d Question # 2

Correct answer: a Question # 3

Correct answer: d Question # 4

Correct answer: b Legal Disclaimer

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